Researchers from The University of Osaka have identified the importance of the signaling molecule and pathways for healthy bone growth, highlighting potential novel treatments for achondroplasia

Osaka, Japan – Achondroplasia, also known as short-limb dwarfism, is associated with neurological symptoms and complications due to narrowing of the skeletal structures surrounding the spinal cord. Despite achondroplasia being the most common cause of dwarfism, the mechanisms underlying the condition remain to be analyzed, meaning that current treatment options are insufficient.

Now, a team at The University of Osaka has created a mouse model of achondroplasia that has advanced understanding of both healthy and abnormal bone growth, highlighting potential therapeutic targets. The findings of their research are due to be published in Nature Communications.

By tracking cell proliferation, the team identified a signaling molecule called FGFR3 and a pathway called CREB as key in regulating bone growth. Growing bones possess a ‘growth plate’ that consists of three distinct layers of chondrocytes, or cartilage cells, known as the resting, proliferating, and hypertrophic zones. Cells move between these zones, dividing into the proliferating zone and then increasing in size in the hypertrophic zone, resulting in healthy bone growth.

The mouse model revealed that cells carrying the genetic mutation associated with achondroplasia accumulate in the resting zone and show abnormal behaviors, which included abnormal patterns of division, migration into the proliferating zone, and gene expression.

“A major challenge in studying the process of chondrocyte differentiation is the difficulty in identifying and analyzing cells at each stage,” explains senior author, Noriyuki Tsumaki. “Here, we overcame this problem using single-cell RNA sequencing. This allows the genes active in a single cell to be identified, and thus each stage of differentiation to be characterized.”

This analysis compared chondrocytes with and without the genetic mutation causing achondroplasia and showed that the major differences were in how cells behaved in the resting zone. This is particularly significant, as previous studies and treatments for this condition have focused exclusively on cells in the proliferating and hypertrophic zones.

“The increased FGFR3 signaling observed in achondroplastic chondrocytes affects signaling through the CREB pathway,” notes lead author, Nanao Horike. “Inhibition of this pathway using a drug called CREB inhibitor 666-15 restored the typical signaling behavior of cells in the growth plate and increased the length of the bone. This tells us that drugs targeting this pathway could have a significant therapeutic effect in achondroplasia.”

This study therefore represents a significant advance in our understanding of how chondrocytes differentiate as bones grow. Moreover, additional discoveries about FGFR3 expression and the CREB pathway provides novel therapeutic targets that, with future research, could prove significant in drug development to minimize the debilitating conditions associated with achondroplasia.
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The article, “Excess FGFR3 signaling in achondroplasia disrupts turnover of resting zone chondrocytes via CREB signaling,” will be published in Nature Communications at DOI: https://doi.org/10.1038/s41467-026-69507-9

About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en